8JZX

SLC15A4 inhibitor complex

Summary for 8JZX

• Entry DOI: 10.2210/pdb8jzx/pdb
• EMDB information: 36754
• Descriptor: lysosomal transporter,ALFA tag,lysosomal transporter, 2-acetamido-2-deoxy-beta-D-glucopyranose, CHOLESTEROL, ... (4 entities in total)
• Functional Keywords: endolysosomal transporter, protein transport-inhibitor complex, protein transport/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 127400.66

Authors

Zhang, S.S.,Chen, X.D.,Xie, M. (deposition date: 2023-07-06, release date: 2023-09-27, Last modification date: 2023-12-13)

Primary citation

Boeszoermenyi, A.,Bernaleau, L.,Chen, X.,Kartnig, F.,Xie, M.,Zhang, H.,Zhang, S.,Delacretaz, M.,Koren, A.,Hopp, A.K.,Dvorak, V.,Kubicek, S.,Aletaha, D.,Yang, M.,Rebsamen, M.,Heinz, L.X.,Superti-Furga, G.
A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.
Nat Commun, 14:6626-6626, 2023

PubMed Abstract: Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease.

PubMed: 37863876
DOI: 10.1038/s41467-023-42070-3

Experimental method

ELECTRON MICROSCOPY (2.5 Å)